High risk of lung cancer in surfactant-related gene variant carriers

Abstract

RationaleSeveral rare surfactant-related genes variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing.ObjectivesWe aimed to study the epidemiology and phenotype of lung cancer in an international cohort of surfactant-related gene (SRG) variant carriers.MethodsWe conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomerase-related gene (TRG) variant carriers.ResultsWe identified 99 SRG adult variant carriers (SFTPA1[n=18],SFTPA2[n=31],SFTPC[n=24],ABCA3[n=14] andNKX2–1[n=12]),including 20 (20.2%) with lung cancer (SFTPA1[n=7]; SFTPA2[n=8],SFTPC[n=3],NKX2–1[n=2] andABCA3[n=0]). Among SRG variant carriers, the odds of lung cancer was associated with age (odds ratio [OR] 1.04 [95% CI 1.01–1.08]), smoking (OR 20.7 [6.60–76.2]) andSFTPA1/SFTPA2variants (OR 3.97 [1.39–13.2]). Adenocarcinoma was the only histological type reported, with PDL1 expression≥1% of tumor cells in 3 cases. Cancer staging was localized (I/II) in 8 (40%) individuals, locally advanced (III) in 2 (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and 3 received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patientsversusTRG patients was 18.1 [7.1–44.7].ConclusionThe high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular CT scan follow-up should be evaluated.